One of the challenges of the science of neurological pharmacology is the control of different types of convulsions (as characterized by the clinical manifestations of the attacks and by specific patterns in the electroencephalogram (EEG)) with pharmaceutical agents. The challenge is heightened by the fact that many anticonvulsant compositions known to the art of pharmacy introduce toxic side effects to patients being administered treatments containing them. A noteworthy example is the impairment of the clinical efficacy of valproic acid for treating symptoms of childhood and adolescent epilepsy by potential embryotoxicity and hepatotoxicity. Pharmaceutical compounds which potentiate (i.e. enhance the potency of) anticonvulsant drugs have been developed and introduced into the field to help meet this heightened challenge. Relatively few compounds are known which have stand-alone convulsion control properties. There is a need for compounds having inherent ability to control seizures or convulsions as well as concurrent properties of potentiating other anticonvulsant drugs without introducing toxic side effects to patients requiring this treatment. It is also highly desirable for an anticonvulsant or neuroprotective agent to be effective against a wide a range of convulsion types. Drugs with different treatment and potentiating profiles enable pharmaceutical and medical practitioners to reach a wider range of patients requiring treatment with greater flexibility and lower risk of harm or discomfort through unavoidable side effects. The present invention in its various aspects helps meet the needs of this challenging field.
Carbetapentane [1-phenylcyclopentanecarboxylic acid 2-(2-diethylaminoethoxy)ethyl ester] has the following structural formula: ##STR1##
This compound belongs to a class of compounds that may be characterized as non-narcotic, non-opiate antitussives, which is a fairly broad class of compounds that are believed to bind to specific sites in the central nervous system (U.S. Pat. No. 4,694,010). Many compounds which fall within this class are available from commercial sources or may be synthesized using well known techniques. The cough suppressant property of carbetapentane, or antitussive compositions containing it, has been disclosed in U.S. Pat. Nos. 4,694,010; 4,898,860; 4,892,877; and 4,906,638.
It has been shown that some non-narcotic, nonopiate antitussives enhance the potency of some anticonvulsant drugs. This effect, often called "potentiation" is manifested by the lowering of the median effective dose (ED.sub.50) of anticonvulsant drugs which are coadministered with a potency enhancing agent. Initial studies in this particular field were conducted to test the diphenylhydantoin potentiating properties of dextromethorphan (D-3-methoxy-N-methylmorphinan), a member of the class of unnatural, non-narcotic opioid enantiomers [(+)-morphinans], see U.S. Pat. No. 4,694,010; Mol. Pharmacol. 23:619-628 and 23:629-640 (1983); and Brain Res. 383:314 (1986). The practical effect of the discovery that non-narcotic compounds such as carbetapentane, caramiphen, dextromethorphan and others would enhance the potency of powerful anticonvulsant agents was that the maintenance dosages of the anticonvulsant agents, which characteristically have toxic side effects, could be reduced and rendered safer. Carbetapentane potentiates some anti-convulsant compounds, such as diphenylhydantoin (phenytoin), and other anti-epileptic hydantoins. In addition, carbetapentane has some anticonvulsant activity independent of its potentiating properties. Some compounds which can be derived from the basic phenylalkanecarboxylic acid structure have been suggested as potential spasmolytic agents (British Patent No. 753,779). The present invention provides compounds with surprising anticonvulsant and nuroprotective properties, and pharmacological methods for using them without dependence, behavioral modification, toxicity, undesirable side effects, or other liabilities that characterize many prior art compounds and treatment modalities.